Cocaine produces many medical and psychiatric complications, and its use is the major cause of drug-related deaths in the United States. Although a tremendous amount of effort has been spent on pharmacologic and other interventions, few treatment options exist for cocaine dependence. Neurotrophic factors have been implicated in activity-dependent plasticity in the adult central nervous system, including the adaptational responses to drugs of abuse. Provocative data have been generated showing the involvement of glial cell line- derived neurotrophic factor (GDNF) in these adaptive responses. GDNF has pronounced effects on central dopaminergic systems, and cocaine addiction is associated with decreases in brain levels of GDNF. One approach to increase GDNF levels at specific brain target sites in a sustained manner is by the use of gene therapy. Current gene therapy vectors allow the long-term expression of GDNF at selected target sites. The overall goal of this application for an Exploratory/Developmental Research Grant (R21) is to express GDNF genes in rat brain using an inducible adenovirus vector, and to determine its therapeutic efficacy in treating cocaine addiction. The first specific aim will test the hypothesis that increasing the expression of GDNF in the nucleus accumbens will reduce the reinforcing effects of cocaine. We will determine if the effects of GDNF hyper-expression on cocaine self-administration are long-lasting, and ascertain the specificity by evaluating whether the motoric effects of cocaine and food-reinforced behavior also are affected. The second specific aim will characterize the effects of viral-mediated GDNF expression on markers of dopaminergic neurotransmission in order to begin to elucidate the mechanisms by which GDNF decreases the reinforcing properties of cocaine. The results of the proposed experiments will establish proof of concept and feasibility and will build the foundation that will allow us to design and carry-out more comprehensive studies characterizing the effects of vector-delivered GDNF on drug self-administration.